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Synlett 2004(6): 1015-1018  
DOI: 10.1055/s-2004-822890
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Hydroxy-7H-benzo[c]fluoren-7-ones

Paulo J. Coelho*, Maria A. Salvador, M. Manuel Oliveira, Luis M. Carvalho
Centro de Química - Vila Real, Universidade de Trás-os-Montes e Alto Douro, 5001-911 Vila Real, Portugal
Fax: +351(259)350480; e-Mail: Pcoelho@utad.pt;
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Publication History

Received 18 December 2003
Publication Date:
25 March 2004 (online)

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Abstract

An efficient synthesis of 2-, 3- and 4-hydroxy-7H-benzo[c]fluoren-7-ones, useful intermediates for the synthesis of photochromic naphthopyrans, is described. The synthetic approach involves the use of oxazolines as activating groups for aromatic ­nucleophilic substitution and starts with readily available di­methoxynaphthaldehydes.

Key words

phenols - fused-ring systems - nucleophilic aromatic substitutions - hydroxy-7H-benzo[c]fluoren-7-ones

    References

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10

Procedure for the Synthesis of 2a-c: A solution of sodium chlorite (3.12 g, 80% purity, 27.6 mmol) in 7 mL of H2O was added rapidly to a warm solution of dimethoxynaphth-aldehyde 1a-c (4.10 g, 19.0 mmol), resorcinol (2.83 g, 21.6 mmol), t-butanol (18.5 mL), HOAc (a few drops) and p-dioxane (16 mL). The reaction mixture was heated 10 min at 85 °C then cooled and concentrated under reduced pressure. CH2Cl2 (20 mL) were added and the organic phase extracted with aq NaOH (2%). The aqueous phase was separated, acidified with HCl and extracted 3 times with CH2Cl2. The organic phases were combined, washed with H2O, sat. NaCl, dried (Na2SO4) and then the solvent was evaporated under reduced pressure to give pure dimethoxynaphthoic acids 2a-c.
1,5-Dimethoxy-2-naphthoic acid (2a): 65% yield, mp 128-130 °C. IR (KBr): 3100-2600, 1697, 1255 cm-1. 1H NMR (CDCl3): δ = 8.14 (d, J = 8.7 Hz, 1 H), 8.05 (d, J = 9.0 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 1 H), 7.53 (t, J = 8.5 Hz, 1 H), 6.97 (d, J = 8.5 Hz, 1 H), 4.15 (s, 3 H), 4.03 (s, 3 H). MS (EI): m/z (%) = 232 (100), 217 (20), 187 (30), 115 (40).
1,6-Dimethoxy-2-naphthoic acid (2b): 70% yield, mp 146-147 °C. IR (KBr): 3100-2400, 1697, 1238 cm-1. 1H NMR (CDCl3): δ = 8.09 (m, 2 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.20 (s, 1 H), 4.16 (s, 3 H), 3.98 (s, 3 H). MS (EI): m/z (%) = 232 (100), 215 (30), 159 (31).
1,7-Dimethoxy-2-naphthoic acid (2c): 75% yield, mp 114-116 °C. IR (KBr): 3100-2500, 1687, 1257 cm-1. 1H NMR (CDCl3): δ = 7.88 (dd, J = 8.5 and 2.5 Hz, 1 H), 7.74 (d, J = 7.0 Hz, 1 H), 7.59 (d, J = 7.0 Hz, 1 H), 7.35 (s, 1 H), 7.24 (d, J = 8.5 Hz, 1 H), 4.08 (s, 3 H), 3.92 (s, 3 H). MS (EI): m/z (%) = 232 (100), 217 (49), 173 (50).

11

Data for oxazolines: 3a: 42% yield. IR (neat): 2965, 1643, 1376 cm-1. 1H NMR (CDCl3): δ = 7.99 (d, J = 8.8 Hz, 1 H), 7.80 (m, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.16 (s, 2 H), 3.97 (s, 6 H), 1.43 (s, 6 H).
3b: 91% yield. IR (neat): 2958, 1637, 1621, 1359 cm-1. 1H NMR (CDCl3): δ = 8.14 (d, J = 9.1 Hz, 1 H), 7.80 (d, J = 8.7 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.16 (dd, J = 2.5 and 9.0 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 4.14 (s, 2 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 1.41 (s, 6 H).
3c: 65% yield. IR (neat): 2965, 1631,1625, 1224 cm-1. 1H NMR (CDCl3): δ = 7.71 (d, J = 9.0 Hz, 1 H), 7.67 (d, J = 8.6 Hz, 1 H), 7.52 (m, 2 H), 7.19 (d, J = 9.0 Hz, 1 H), 4.16 (s, 2 H), 3.98 (s, 3 H), 3.93 (s, 3 H), 1.43 (s, 6 H).

12

Data for oxazolines 4a: 30% yield. 1H NMR (CDCl3): δ = 8.33 (d, J = 8.7 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.48-7.34 (m, 5 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.23 (t, J = 8.5 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 4.03 (s, 3 H), 3.72 (s, 2 H), 1.21 (s, 6 H).
4b: 36% yield. 1H NMR (CDCl3): δ = 7.75 (m, 2 H), 7.54 (d, J = 9.0 Hz, 1 H), 7.45-7.32 (m, 5 H), 7.17 (d, J = 2.5 Hz, 1 H), 7.04 (dd, J = 2.5 and 9.5 Hz, 1 H), 3.92 (s, 3 H), 3.69 (s, 2 H), 1.19 (s, 6 H).
4c: 39% yield. 1H NMR (CDCl3): δ = 7.79 (m, 2 H), 7.63 (d, J = 8.5 Hz, 1 H), 7.45-7.35 (m, 5 H), 7.17 (d, J = 2.5 and 9.1 Hz, 1 H), 6.94 (d, J = 2.5 Hz, 1 H), 3.71 (s, 2 H), 3.68 (s, 3 H), 1.19 (s, 6 H).

13

Procedure for the Synthesis of 5a-c: A solution of oxazoline 4a-c (0.69 g, 2.08 mmol) in MeI (10 mL) was stirred at r.t. overnight and the excess of MeI removed under reduced pressure. To the crude MeI salt, were added MeOH (12 mL) and NaOH 20% (12 mL) and the mixture heated to reflux for 12 h. The solution was extracted with Et2O and the organic layer discarded. The aqueous layer was acidified with HCl (aq), extracted with Et2O, dried (Na2SO4) and concentrated to give the corresponding methoxy-1-phenyl-2-naphthoic acid. Without further purification, H2SO4 (5 mL) was added. After stirring for 5 min at r.t. the resulting dark colored solution was poured into ice (50 g) and then extracted with Et2O (3 × 50 mL). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure to give pure ketone 5a-c as red solids.
5a: 97% yield, mp 192-193 °C. IR (KBr): 1706, 1263 cm-1. 1H NMR (CDCl3): δ = 8.27 (d, J = 8.5 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.54-748 (m, 2 H), 7.28 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 7.5 Hz, 1 H), 4.02 (s, 3 H). MS (EI): m/z (%) = 260 (100), 245 (20), 217 (53), 189 (50).
5b: 86% yield, mp 146-147 °C. IR (KBr): 1708, 1272 cm-1. 1H NMR (CDCl3): δ = 8.36 (d, J = 9.0 Hz, 1 H), 7.93 (d, J = 7.5 Hz, 1 H), 7.68-7.59 (m, 2 H), 7.47 (m, 1 H), 7.22 (m, 2 H), 7.11 (d, J = 2.5 Hz, 1 H), 3.92 (s, 3 H). MS (EI): m/z (%) = 260 (100), 217 (45), 189 (50).
5c: 78% yield, mp 126-128 °C. IR (KBr): 1725, 1274 cm-1. 1H NMR (CDCl3): δ = 7.92 (d, J = 7.5 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 1 H), 7.72-7.67 (m, 2 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.54-7.50 (m, 2 H), 7.31-7.24 (m, 2 H), 4.02 (s, 3 H). MS (EI): m/z (%) = 260 (100), 217 (60), 189 (45).

14

Procedure for the Synthesis of 6a-c: A mixture of ketone 5a-c (0.34 g, 1.31 mmol), HOAc (2.5 mL) and HBr 47% (5 mL) was heated under reflux for 5 h. After cooling the reaction mixture was poured into 100 mL of H2O and extracted with Et2O (3 × 50 mL). The combined organic layers were extracted 3 times with NaOH (5%, 20 mL) and the organic phase discarded. The aqueous phase was acidified with HCl 10%, and extracted with Et2O (3 × 50 mL). The combined organic layers were dried (Na2SO4) and the solvent evaporated under reduced pressure giving the pure hydroxybenzofluorenones 6a-c.
4-Hydroxy-7H-benzo[c]fluoren-7-one (6a): 63% yield, mp 258-260 °C. IR (KBr): 3280, 1691 cm-1. 1H NMR (acetone-d 6): δ = 9.39 (s, 1 H), 8.34 (d, J = 8.5 Hz, 1 H), 8.23 (d, J = 7.5 Hz, 1 H), 8.17 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 8.5 Hz, 1 H), 7.66-7.62 (m, 2 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H). 13C NMR (CDCl3/CD3OD): δ = 195.4, 153.9, 145.2, 142.3, 134.5, 134.2, 131.7, 129.8, 129.5, 128.3, 128.2, 124.1, 123.7, 123.3, 118.1, 115.8, 110.4. MS (EI): m/z (%) = 246 (100), 218 (22), 189 (70). HRMS: Calcd for C17H10O2: 246.0681; found: 246.0673.

3-Hydroxy-7H-benzo[c]fluoren-7-one (6b): 93% yield, mp 264-265 °C. IR (KBr): 3230, 1685 cm-1. 1H NMR (acetone-d 6): δ = 9.21 (s, 1 H), 8.61 (d, J = 9.0 Hz, 1 H), 8.23 (d, J = 7.5 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.62 (m, 3 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.37 (dd, J = 2.5 and 9.1 Hz, 1 H), 7.34 (d, J = 2.5 Hz, 1 H). 13C NMR (CDCl3/CD3OD): δ = 194.9, 157.2, 144.7, 143.3, 140.3, 134.8, 134.2, 129.0, 128.5, 127.6, 126.5, 123.6, 123.4, 123.1, 120.3, 120.1, 110.7. MS (EI): m/z (%) = 246 (100), 218 (15), 189 (45). HRMS: Calcd for C17H10O2: 246.0681; found: 246.0676.
2-Hydroxy-7H-benzo[c]fluoren-7-one (6c): 91% yield, mp 263-265 °C. IR (KBr): 3276, 1685 cm-1. 1H NMR (acetone-d 6): δ = 8.11 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 2.2 Hz, 1 H), 7.93 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.63 (m, 2 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.32 (dd, J = 2.3 and 8.9 Hz, 1 H). 13C NMR (CDCl3/CD3OD): δ = 195.3, 156.5, 145.4, 141.5, 134.5, 134.3, 133.2, 131.9, 131.0, 130.1, 129.7, 128.1, 123.8, 122.8, 120.8, 116.9, 106.4. MS (EI): m/z (%) = 246 (100), 217 (5), 189 (40). HRMS: Calcd for C17H10O2: 246.0681, found: 246.0678.